Animals, including humans and other mammals, can be afflicted by a number of bone related disorders such as osteoporosis and Paget's disease. Although the cause of bone related disorders is poorly understood, it is believed that there may be an imbalance between bone formation and bone resorption (bone breakdown). For example, in animals suffering from an osteoporotic condition, bone resorption exceeds bone formation. The complex process of bone formation and bone resorption may be mediated by two cell types: osteoblasts, which is involved in bone formation and osteoclasts, which is involved in bone resorption.
A promising therapeutic approach to the treatment of bone related disorders would be the administration of agents which have been designed to modify the balance between the rate of bone formation and the rate of bone resorption in such a manner that the ratio of the former to the latter is increased, resulting in no net bone loss. For example, the bone loss may be suppressed by inhibiting bone resorption (e.g. inhibiting activity of osteoclasts) or inducing bone formation (e.g. inducing activity of osteoblasts). After the previously occurred bone losses have been restored, a steady state is reached where the rate of bone production and rate of bone resorption are equal. Such a modification may be effected by stimulating the physiological mechanism of bone deposition, i.e., bone formation, or by retarding the mechanism of bone resorption, or both. Drugs presently in use or in the experimental stages for accomplishing these purposes include hormone replacement therapy, selective estrogen receptor modulators (SERMs) (e.g., Raloxifene), bisphosphonates (e.g., alendronate) and calcitonin. These therapeutic treatments reduce bone resoption by decreasing osteoclast generation and reducing osteoclast activity (Canalis E, 2000, J Clin Invest., 106(2): pp 177-179). Although the resulting decrease in bone resorption leads to small increases in bone mineral density (BMD), these drugs do not increase bone matrix deposition or bone volume (Tashjian, A. H., et. al., J. Bone Miner. Res. 17: 1151-1161. 2002). One agent, parathyroid hormone (PTH), when administered once daily stimulates bone matrix formation (Cosman, F. et. al., Calcif. Tissue Int. 62: 475-480, 1998, Neer, R. M., et. al., N. Engl. J. Med. 344:1434-1441, 2001)
PTH and its biologically active fragment PTH 1-34, have been recognized since 1930 that they could exert strong bone forming effects. Interest in bone forming ability of PTH was revived in 1970s and 1980s after numerous clinical studies indicated a bone forming activity of PTH primarily within trabecular bone while with little or no effects on cortical bone (Bauer et al, 1929, J Exp Med, 49: pp 145-162, Selye H, 1932, Endocrinology, 16: pp 547-558, Dempster et al., 1993, Endocrine Reviews, 14(6): pp 690-709, Bauer et al, 1929, J Exp Med, 49: pp 145-162; Selye H, 1932, Endocrinology, 16: pp 547-558). More recent work has shown that the increase in bone formation by PTH increases not only bone mass but improves bone architecture and biomechanical properties (Brommage, R. et. al., J. Clin. Endocrinol. Metab. 84:3757:3763, 1999., Sato, M. et. al., Osteoporos. Int. 11:871-880, 2000., Burr, D. B., et. al., J. Bone Miner. Res. 16:157-165, 2001., Jerome, C. P., et. al., Bone 28:150-159, 2001). Although PTH has these anabolic (bone forming) properties its actions are complex because it can have catabolic (bone degradation) activities under certain treatment regimens (Dempster, D. W. et. al., Endocrine Reviews, 14:690-709, 1993).
A significant need exists to identify novel gene(s) and their protein products for the elucidation of the molecular mechanism of bone modulation or formation, for the screening and development of new drugs, for diagnosis, prognosis, prevention, and treatment of bone development and bone loss disorders, and evaluation of therapies for bone related disorders such as osteoporosis. Furthermore, there is currently a need in the industry for models of bone related disorders, including animal models, to enable screening and identification of compounds for the treatment of these diseases. The present invention overcomes these problems and provides the needed tools.